A prominent hypothesis in cognitive neuroscience is that memories are organized and made permanent in the cerebral cortex via temporary involvement of the hippocampus, a phenomenon called systems consolidation. Although key roles for the cortex and hippocampus are well established, very little is known about the nature of the underlying neural memory representations and how they change during consolidation. Yet, to address disorders of thought and organization of knowledge, it will be crucial to understand how memories are encoded, organized, and consolidated in the normal brain. The proposed experiments are designed to pioneer a new approach to this area by examining current theories of systems memory consolidation by combining state-of-the-art multichannel neuron recording in animals as they learn and remember a series of what- happened-where associations, as well as state-of-the-art techniques for reversible neural inactivation to examine functional interactions between the hippocampus and cortex. Specific Aim 1 will characterize the nature and organization of neural ensemble memory representations in the cortex and hippocampus and the development of cortical representations in the absence of hippocampal function. Specific Aim 2 will examine the time-limited role of the hippocampus in the organization and stabilization of cortical memory representations following learning. Specific Aim 3 will examine the role of consolidation at the cellular and synaptic level on the persistence of neural memory representations in the hippocampus and cortex. These studies will provide the first examination of systems consolidation at the level of neural representations, challenging current views and leading to new insights about this important phenomenon in cognitive function. PUBLIC HEALTH RELEVANCE: Our understanding of cognitive disorders and the eventual development of treatments depends crucially upon an understanding of the cognitive and neural mechanisms that underlie normal cognition; for example, abnormal thought patterns in schizophrenia, as well as other cognitive disorders, reflects an underlying disorganization of the neural machinery that stores and consolidates memories in the schemas that compose our knowledge of the world. The proposed work will pioneer a new understanding about how memories are represented in neural circuitry and about how neural representations are organized into schemas that guide cognition in daily life. Because the hippocampus and adjacent cortical areas are compromised in multiple major mental disorders, an understanding the functional circuitry of these areas is particularly important.